Family of Errant Genes Is Found to Be Related To Variety of Skeletal Ills

By NATALIE ANGIER

Published: November 1, 1994

FORGET the great human heart and brain, the eyes that see sweeping vistas, the lips that declare "I am"; the real thing standing between us and primordial ooze is the human skeleton. Built of 206 bones, 29 in the skull alone, the skeleton is a living cathedral of ivory vaults, ribs and buttresses -- a structure at once light and strong, flexible and firm.

Yet like those toy kits requiring self-assembly, the skeleton is also so complicated that many things can and do go wrong with it during development. Disorders that affect the growth of the body's bones are among the most common of all birth defects. For example, at least one in 3,000 babies suffers from any of 100 different syndromes that cause the sutures of the skull plates to fuse prematurely.

Such conditions result in heads that are too tall or too flat or grossly asymmetric or shaped like a cloverleaf, all requiring surgery soon after birth to relieve pressure within the cranial cavity. Dwarfism, syndactyly, limb deformities, the curvature of the spine called scoliosis -- the list of deviations from the standard skeletal diagram is long and motley.

In recent weeks, however, scientists have reported a spectacular series of discoveries showing that defects in the same group of genes may be responsible for many different disorders of the skeleton. They have linked disorders as varied as achondroplasia -- the commonest genetic form of dwarfism -- and three diseases that affect the face, skull, hands and feet to mutations in a class of genes called fibroblast growth factor receptors. These genes, which were originally identified for their role in the growth of connective skin cells, or fibroblasts, have been known and studied for years. But only within the past couple of months have they been shown in their mutant form to be the cause of human skeletal disorders.

The discoveries have come so fast that even those in the field have barely been able to keep abreast of the results. The first link was announced in late July, when scientists from the University of California at Irvine said that achondroplastic dwarfism resulted from a defect in the gene that allows the body to produce fibroblast growth factor receptor 3 (so numbered because it was the third of the growth factor family to have been discovered, in the 1980's).

In September, researchers from the Institute of Child Health in London announced in the journal Nature Genetics that Crouzon syndrome, a cause of premature fusion of the skull plates, was associated with defects in the gene that makes fibroblast growth factor receptor 2. And in today's issue of Nature Genetics, two different teams announce yet more evidence of malfeasance among the growth factor receptor clan: in one case, scientists said a mutation in the gene for fibroblast growth factor receptor 1 causes Pfeiffer syndrome, which also leads to the untimely fusion of the cranial sutures, but in addition makes the thumbs and toes very wide. In the second, a team again linked receptor No. 2 to a skeletal problem, this time to Jackson-Weiss syndrome, which prompts the development of skull and foot anomalies.

"This has been the most exciting time of my entire career," said Dr. Maximilian Muenke of the University of Pennsylvania School of Medicine in Philadelphia, the lead author on the report about Pfeiffer syndrome. "From seeing my first Pfeiffer patient eight years ago, to having the gene defect known and to learning that three other skeletal defects result from mutations in the same gene family -- it's absolutely thrilling."

The troika of implicated genes all do similar things in the body: they produce receptor proteins that sit on the surface of cells, including the cells of the bones, and respond to stimulatory signals from growth factors floating around them. Of great astonishment to scientists, the receptors are found on many different cell types of the body and are known to be essential to the growth and maturation of many tissues and organs; yet the impact of a mutation on the receptors' function appears to hit bone development the hardest and most consistently.

Through analyzing the genes and tracing their role in these different cranio-skeletal conditions, scientists may get a handle on how independent yet related genes work together to construct the great osteotic Lego set of the body.

The latest findings also pose a significant challenge to the fledgling field of bioethics, however. With the mutations now identified, researchers may soon have prenatal tests available to identify an embryo with a skeletal defect early enough to permit the mother to have an abortion if she chooses. But unlike other genetic disorders that may be screened for prenatally, the skeletal syndromes in most cases are neither lethal nor excessively debilitating. They do not impair intelligence or lead to great physical pain. Instead, they make people look unusual or deformed or funny.

Hence, the findings may force scientists, ethicists and parents to confront the question of what exactly distinguishes a genetic disease from a genetic condition, an esthetic deviation from the norm, and to decide how far they are willing to go to fix what is not unequivocally broken.